AIDS (acquired immunodeficiency syndrome), first reported in the United States in 1981, is a worldwide epidemic. AIDS is caused by the human immunodeficiency virus (HIV), which acts to progressively destroy the body's ability to fight infections and certain kinds of cancers by killing or damaging cells of the body's immune system. By some estimates, nearly one million people in the United States may be presently infected with HIV.
When AIDS first surfaced in the United States, there were no medicines to combat HIV; however, over the past 11 years, drugs have been developed to fight both HIV infection and its associated infections and cancers. These drugs can be categorized into different classes based upon their mode of action. Three classes of anti-HIV drugs, although acting at different times during the viral life cycle, interrupt viral replication after the virus has infected a T-cell. These classes of anti-HIV medications include nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Drugs falling into these various classes include AZT, zalcitabine, dideoxyinosine, stavudine, and lamivudine (nucleoside reverse transcriptase inhibitors); delvaridine, nevirapine, and efravirenz (non-nucleoside reverse transcriptase inhibitors), and ritonavir, saquinivir, and indinavir (protease inhibitors). However, there is another class of antiretroviral agents, the entry inhibitors, that work differently than the previously described conventional classes of anti-HIV drugs. Rather than working against HIV post T-cell infection, an entry inhibitor actually prevents HIV from infecting a T-cell in the first place. More specifically, entry inhibitors work by attaching themselves to proteins on the surface of T-cells or proteins on the surface of HIV. In order for HIV to bind to T-cells, the proteins on HIV's outer coat must bind to the proteins on the surface of T-cells. Entry inhibitors prevent the occurrence of such binding. Some entry inhibitors target the gp120 or gp41 proteins on HIV's surface, while other entry inhibitors target the CD4 protein or the CCR5 or CXCR4 receptors on a T-cell's surface. Entry inhibitors include T-20 (also referred to as enfuvirtide), PRO-542, SCH-C, SCH-D, and T-1249. To date only one entry inhibitor, T-20, has been approved by the FDA. T-20 inhibits the fusion of HIV-1 with CD4+ cells.
Entry inhibitors (including fusion inhibitors) are a promising new type of anti-HIV drug. Entry inhibitors like T-20 are particularly attractive to HIV-positive individuals whom have not responded using the traditional anti-HIV drugs, e.g., PIs, NRTIs and NNRTIs, either alone or in combination therapy. T-20 is a 36 amino acid synthetic peptide having an acetylated N-terminus and the C-terminus modified as the carboxamide. T-20 (FUZEON™) received marketing approval from the FDA in March 2003. Unfortunately, despite high expections, sales of the drug have been hampered by its steep prices and more importantly, its difficulty of administration. T-20 is injected under the skin two times a day. Such frequent patient dosing can be very unattractive to patients—many of whom ultimately fail to maintain the necessary dosing regime, due to the high frequency of dosing, mode of administration, and general fatigue associated with preparing and administering the drug. Indeed, 98% of FUZEON™ patients reported at least one instance of painful or troublesome local injection site reactions (ISR). ISR symptoms include pain/discomfort, induration, erythema, and nodules/cysts. Reported hypersensitivity reactions include rash, fever, nausea and vomiting, chills, rigors, and hypotension. It has become increasingly clear that drugs such as T-20 are not easy drugs for patients to take. The pain associated with ISR is considered mild to moderate, and the mean duration of each ISR is around 7 days. Moreover, resistance to T-20 can develop fairly quickly if full doses are not taken on a consistent basis. (GMHC Treatment Issues, Vol. 17, No. 1/2, January/February 2003). Thus, there is a need in the art for improved anti-HIV agents, and in particular, improved entry inhibitors, having longer circulating half-lives in the bloodstream whilst maintaining a measurable, and more preferably a significant, degree of activity, thereby allowing less frequent patient dosing and thus a reduced occurrence of local injection site reactions. This invention meets these needs.